UC San Diego

Within the nervous system, the spinal cord plays vital roles both at the initial steps of receiving and processing incoming sensory information, and at the final stages of executing appropriate motor plans. Spinal neural networks are sufficient to produce corrective sensorimotor reflexes and locomotor central pattern generator activity, but also must interface with the brain to produce more nuanced and elaborate behavior. Consequently, a diverse array of spinal interneurons mediate these functions. Significant studies have delineated spinal neurons into cardinal classes with distinct developmental origins and functions. However, recent studies have uncovered extensive molecular and circuit diversity within each cardinal class. As a result, because each cardinal class is comprised of a mixture of subpopulations, it has been difficult to interpret which aspects of each cardinal class are most salient to its function. This dissertation describes a series of original work that aims to identify a unifying logic for spinal neuron diversification across cardinal classes. The first chapter consolidates recent work on spinal neuron characterization, with a focus on molecular and circuit diversity within single cardinal classes. The second chapter examines molecular diversity conserved across heterogeneous populations of spinal neurons. We found broad genetic signatures which divide the spinal cord into sensory-motor, local-long range, and inhibitory-excitatory groups of neurons. The local-long range signature corresponded to neuronal birthdate and divided each cardinal class into their local and projection subsets. Thus, many aspects of diversity within each cardinal class can be tracked with the same molecular signatures, greatly simplifying the task of identifying discrete functional cell types. The third chapter provides an initial characterization of transgenic mouse lines developed to label the local and long-range groups of spinal neurons identified in chapter two.

In summary, this work identifies a genetic axis which governs aspects of spinal neuron diversity. This genetic axis is organized temporally, reflecting the birthdate of spinal neurons. It corresponds to whether the neuron projects locally or long-range. This genetic axis is orthogonal to the previously defined cardinal classes, and when used together predict many aspects of spinal neuron attributes, including location, neurotransmitter, and synaptic outputs.